Peptide Bond Modification for Metal Coordination: 2. Metal-Binding Properties of Peptide-Derived Pentaaza-Macrocyclic Templates

Conformation templates have been applied to elucidation of receptor-bound conformation, design of peptidomimetics, construction of combinatorial libraries, and de novo peptide and protein design. We are exploring pentaaza-macrocyclic templates (Figure 1) in conjunction with metal coordination as a means to preorganize peptides for probing molecular recognition. One consideration is that the peptide backbone of cyclic penta-peptides, used by the Kessler group and others as receptor probes, can be readily transformed to chiral pentaaza-macrocycles via selective reductions of the amide bonds [1] with side chains displayed around the macrocyclic scaffold in a defined geometrical manner. In addition, the pentaazamacrocycle is an excellent ligand system for coordination of various metals [2] that can preorganize the molecular structures even further to help define the conformation responsible for biological activity. We are also exploring the effects of the chiral pendant side chains on the metal-binding properties and related molecular recognition of the azacrown scaffold.